Background: Aryl Hydrocarbon Receptor Interacting Protein-Like 1 (AIPL1) interacts with NUB1 and restricts the entry of NUB1 protein into the nucleus. The interferon-induced NEDD8 ultimate buster (NUB1) protein causes degradation of neddylated and FAT10ylated proteins through the ubiquitin proteasome system. We observed AIPL1 were frequently down-regulated in various cancers compared to normal tissues. The mechanistic roles of AIPL1 and NUB1 protein in cancer cell cycle regulation remain unexplored. Results: Meta-analysis of cancer databases revealed that expression transcripts of chaperones, including AIPL1, were down-regulated in lung, pancreatic cancer and breast cancer relative to the adjacent normal tissues. Opposite levels of both AIPL1 and NUB1 transcripts were observed in the breast cancer. So it triggers the in vitro experiments using breast cancer cells. METABRIC breast cancer clinical cohort highlighted that patients with low NUB1 transcripts had poor survival in the ER-negative subgroup (but not in ER-positive) of breast cancer patients: hazard ratio (HR)=0.66, 95p confidence interval (CI)=0.5-0.87, p=0.003 and triple negative subgroup of breast cancer patients: HR=0.67, 95p CI=0.47-0.96, p=0.028. NUB1 silencing significantly inhibits in vitro cell growth in MDA-MB-231 and MCF7 under hypoxia. AIPL1 protein forms multimers in cancer cells. NUB1 protein moved into the nucleus in hypoxia (0.1p O2 48hrs) with final confluency at 80-90p. p21 (marker of senescence) & p27 (marker of cell cycle arrest) accumulated in NUB1-silent MDA-MB-231 and RCC4 cells. It suggested that low NUB1 nuclear localisation in hypoxia cause cancer cell cycle arrest. In MDA-MB-231 cell, upon hypoxia, neddylation inhibitor (MLN4924) treated and siNUB1 transfected cells showed decreased CUL1 and further accumulated p21 & p27. The evidence suggested lower neddylated CUL1 and reduced NUB1 cooperatively stabilise p21 and p27 as the substrate of CUL1-ubiquitin ligase. The neddylation inhibitor MLN4924 treated and NUB1 knockdown group exhibited more cells in sub-G1 stage as compared to the control group. In connection to higher p21/p27, it is associated with prolonged arrested cellular aging with depletion. After silencing of NUB1, the increases in cell death of cancer cells upon hypoxia happen through the neddylation-dependent CUL1-p27-p21 and CUL2-VHL axis. We then demonstrated that HIF1α protein could be both neddylated and FAT10ylated upon reoxygenation. In a tissue microarray study of breast cancer, lower cytoplasmic expression (n=57) had worse overall survival than higher cytoplasmic expression (n=57): HR=1.779, 95p CI=1.006-3.346, p=0.048. Conclusions: AIPL1 and NUB1 proteins exert a role in cell cycle regulation in breast cancer. Low cytoplasmic NUB1 levels are observed in the G1-S transition of cancer cells. NUB1 depletion causes G0/G1 phase arrest due to CUL1 and CUL2 ubiquitin E3 ligase-dependent pathways.
Introduction Aryl Hydrocarbon Receptor Interacting Protein-Like 1 (AIPL1) protein interacts with and restricts NEDD8 ultimate buster-1 (NUB1) protein from entering nucleus. The interferon-induced NUB1 protein causes degradation of neddylated proteins through the ubiquitin proteasome system. The AIPL1 transcripts were down regulated in various cancers compared to adjacent normal tissues. The mechanistic roles of AIPL1 and NUB1 protein in cancer cell cycle regulation remain unexplored. Material and methods Protein expression was examined by immunoblotting and immunochemistry. Cells were cultured in the recommended conditions. The NUB1 monoclonal antibody and the DAKO Envision Plus system were used to evaluate FFPE. Survival curves was analysed by kaplan meier methods and compared by the log rank test. All statistical tests were two sided. Results and discussions The meta-analysis of cancer dataset showed the transcripts expression of AIPL1 were down regulated in lung, pancreatic and breast cancer in relative to the adjacent normal tissues. The upregulated NUB1 transcripts were observed in the breast cancer. METABRIC cohort highlighted that patients with low NUB1 transcripts had a poorer survival in the ER-negative subgroup of breast cancer patients [hazard ratio (HR)=0.66, 95% confidence interval (CI)=0.5–0.87, p=0.003] and triple negative subgroup (HR=0.67, 95% CI=0.47–0.96, p=0.028). NUB1 knockdown inhibits in vitro cell growth in MDA-MB-231. AIPL1 protein forms multimers in cancer cells. NUB1 protein moved into the nucleus in hypoxia (0.1% O 2 48 hours). p21 and p27 proteins accumulated in NUB1-knockdown MDA-MB-231 cells. The prolonged G 0 /G 1 cell cycle arrests resulted in cell death through the neddylation-dependent CUL1-p27-p21 and CUL2-VHL axis. We also demonstrated that HIF1α protein could be neddylated upon reoxygenation. In a retrospective study of Oxford breast cancer cohort, the lower cytoplasmic expression (n=57) prognosed worse overall survival than higher cytoplasmic expression (n=57) (HR=1.779, 95% CI=1.006–3.346, p=0.048). Conclusion NUB1 protein depletion cause G 0 /G 1 cell cycle arrest in breast cancer. Low cytoplasmic NUB1 protein prognosed worse survival of breast cancer patients. NUB1 depletion causes cell cycle arrest via the deactivated ubiquitin E3 ligase pathway.
The effect of citrate phosphate dextrose (CPD) blood transfusion on the acid base, glucose and electrolyte status of VLBW infants was studied in infants aged 1–7, 8–20 and > 20 days; a 4th group composed of infants > 20 days subjected to a second transfusion was also studied. All the infants remained clinically well during and after the transfusion. Only the infants in the group 1–7 days experienced a signifcant fall in ionic Ca and PO<sub>2</sub>. No significant change in all the other parameters studied was observed. In the other groups of infants studied, the changes observed were not significant, and became less with increasing age and repeat transfusion. VLBW infants apparently tolerate CPD blood transfusion well.
Abstract A newly developed branded generic of a moxifloxacin (MOX) 400‐mg tablet formulation was manufactured prior to this study. A bioequivalence (BE) study was done to assess the pharmacokinetics of the formulation using a randomized, open‐label, 2‐period crossover, 2‐sequence, and single‐dose experiment. Thirty healthy male volunteers were recruited. The test formulation, Flonoxin 400 mg, was compared with the reference formulation, Avelox 400 mg. The pharmacokinetic parameters of MOX were calculated based on the plasma drug concentration‐time profile. Noncompartmental analysis was performed to determine its safety and tolerability. The 90% confidence intervals (CIs) were 88.5%‐104.6%, 96.1%‐101.1%, and 96.8%‐100.7% for C max , AUC 0‐t , and AUC 0‐inf , respectively. All CIs were within the 80.0%‐125.0% boundary, thus fulfilling the acceptable BE criteria according to the ASEAN guidelines.
The capabilities of tumour cells to survive through deregulated cell cycles and evade apoptosis are hallmarks of cancer. The ubiquitin-like proteins (UBL) proteasome system is important in regulating cell cycles via signaling proteins. Deregulation of the proteasomal system can lead to uncontrolled cell proliferation. The Skp, Cullin, F-box containing complex (SCF complex) is the predominant E3 ubiquitin ligase, and has diverse substrates. The ubiquitin ligase activity of the SCF complexes requires the conjugation of neural precursor cell expressed, developmentally down-regulated 8 (NEDD8) to cullin proteins. A tumour suppressor and degrading enzyme named NEDD8 ultimate buster 1 (NUB1) is able to recruit HLA-F-adjacent transcript 10 (FAT10)- and NEDD8-conjugated proteins for proteasomal degradation. Ubiquitination is associated with neddylation and FAT10ylation. Although validating the targets of UBLs, including ubiquitin, NEDD8 and FAT10, is challenging, understanding the biological significance of such substrates is an exciting research prospect. This present review discusses the interplay of these UBLs, as well as highlighting their inhibition through NUB1. Knowledge of the mechanisms by which NUB1 is able to downregulate the ubiquitin cascade via NEDD8 conjugation and the FAT10 pathway is essential. This will provide insights into potential cancer therapy that could be used to selectively suppress cancer growth.
Over the past eight decades, numerous research has been conducted on the extraction of Zingiber zerumbet rhizome. The mini-review includes information on the pharmacological properties of zerumbone extracted from Z. zerumbet rhizome and the extraction methods conducted over the previous 80 years. Zerumbone is recognised as having a proven pharmacological effect and is a significant medicinal component used to treat various ailments. The pharmacological values are stated based on the research findings. The extraction method and technology are essential to extract zerumbone. Thus, the review helps the reader keep up with the history of each technique or technology used in extracting zerumbone from Z. zerumbet rhizome, starting with conventional technology and moving toward advanced technology.
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